Several lines of evidence imply that autism, epilepsy, and schizophrenia may share some underlying brain abnormalities. Recent genetic studies suggest that mutations of Caspr2, gene product of CNTNAP2, increase the disease risk of these common manifestations. At the protein level, the role of Caspr2 in the rodent peripheral nervous system is established. In the human CNS, however, no information on the role of this protein and its neuronal location is thus far available. Recent studies suggest that Caspr2 is a key molecule in cell-cell interactions important for normal neuronal function and cortical development. To understand the structure of this protein and its functions in the human brain, we propose the following: 1) Study the three-dimensional structure of the extracellular domain of Caspr2. As the atomic structure of a protein drives its function, Caspr2 structure will enable us to improve our understanding of the biology of this neuronal protein and to predict how mutations linked to a disease state affect Caspr2 structure and function, thus setting the basis for future drug targets identification for epilepsy and autism. 2) Investigate the role of Caspr2 in hippocampal neurons and the biochemical and cellular consequences of mutations of human Caspr2 linked to ASD. Because mutations found in the human population affect the biological function of Caspr2, analysis of these mutations promises to yield critical insights into the neuronal anomalies that give rise to aberrations in neuronal connectivity, and may provide a basis for designing specific therapeutic interventions.